Day: September 23, 2013

Researchers at the University at Buffalo have discovered a new understanding of atherosclerosis in humans that include a key role for stem cells that promote inflammation.

Published in the journal PLOS One, this work extends to humans previous findings in lab animals by researchers at Columbia University that showed that high levels of LDL (“bad”) cholesterol promote atherosclerosis by stimulating production of hematopoietic stem/progenitor cells (HSPC’s).

“Our research opens up a potential new approach to preventing heart attack and stroke, by focusing on interactions between cholesterol and the HSPCs,” says Thomas Cimato, lead author on the PLOS One paper and assistant professor in the Department of Medicine in the UB School of Medicine and Biomedical Sciences.

Cimato noted that the role of stem cells in atherosclerosis could lead to the development of a useful therapy in combination with statins or to a novel therapy that could be used in place of statins for those individuals who cannot tolerate them.

In humans, high total cholesterol recruits stem cells from the bone marrow into the bloodstream. The cytokine IL-17, which has been implicated in many chronic inflammatory diseases, including atherosclerosis, is responsible for the recruitment of HSPCs. IL-17 boosts levels of granulocyte colony stimulating factor (GCSF), which induces the release of stem cells from the bone marrow.

According to Cimato, they observed that statins reduce the levels of HSPCs in the blood but not every subject responded similarly. “We’ve extrapolated to humans what other scientists previously found in mice about the interactions between LDL cholesterol and these HSPCs,” explains Cimato.

The fact that a finding in laboratory animals holds true for humans is noteworthy, adds Cimato. “This is especially true with cholesterol studies,” he says, “because mice used for atherosclerosis studies have very low total cholesterol levels at baseline. We feed them very high fat diets in order to study high cholesterol but it isn’t [sic] easy to interpret what the levels in mice will mean in humans and you don’t know if extrapolating to humans will be valid.”

Cimato added that the LDL concentrations in the blood of mice in their studies is much higher than what is found in patients who come to the hospital with a heart attack or stroke.

“The fact that this connection between stem cells and LDL cholesterol in the blood that was found in mice also turns out to be true in humans is quite remarkable,” he says.

Cimato explains that making the jump from rodents with very high LDL cholesterol to humans required some creative steps, such as the manipulation of the LDL cholesterol levels of subjects through the use of three different kinds of statins.

The study involved monitoring for about a year a dozen people without known coronary artery disease who were on the statins for two-week periods separated by one-month intervals when they were off the drugs.

Cimato and his group found that LDL cholesterol modulates the levels of stem cells that form neutrophils, monocytes and macrophages, the primary cell types involved in the formation of plaque and atherosclerosis.

The next step, he says, is to find out if HSPCs, like LDL cholesterol levels, are connected to cardiovascular events, such as heart attack and stroke.